GGT: Cancer, Oxidative Stress and Mortality

As on other Science Library pages, we do not present a lengthy narrative on each body system affected by cancer, but rather will briefly summarize or quote the most relevant take-home points and/or research conclusions from each study. Article titles are linked to abstracts archived at the U.S. National Library of Science. Many articles also have Full free text PDF links. Our Iron Science Library pages include:

In this 2010 study in the U.K., the oncology researchers stated, "It has been reported that there is an increased risk of cancer in individuals with elevated levels of serum gamma-glutamyl transferase (GGT)." The researchers examined data from the Guernsey Cohort Study, which recruited 4,714 women over the age of 32 who attended a cancer research laboratory in Guernsey. Initial baseline measurements, including GGT, were obtained during recruitment. Women with a previous diagnosis of most cancers and women in which new cancers were observed at baseline were excluded from the analysis."GGT was measured in sera (blood serum)from 1,803 normal women. Among these women, 251 subsequently developed cancer, of whom 96 developed breast cancer." After adjusting for relevant factors, "there was a highly significant relationship between elevated GGT and breast cancer risk. In the highest quartile(i.e. highest 25% of GGT), the hazard ratio (HR) was 2.17..." [more than a two-fold risk of breast cancer] "When subdivided by menopausal status, there was a reduced non-significant effect in postmenopausal women, whereas for premenopausal women in the highest quartile, HR was 3.81..." [nearly a four-fold risk in premenopausal women] "Premenopausal women with serum GGT levels above the normal range had a significantly elevated HR of 4.90 (95% CI: 1.86, 12.94)."[nearly a five-fold risk] [Healthy-e-Iron note: Tables 4 & 5 from from this study and a graphic derived from the findings are below]

Table 4 Hazard ratio for breast cancer risk in relation to level of serum GGT (adjusted by age, age at first birth/nulliparity, age at menarche, height and weight)

Table 5 Breast cancer risk and GGT by menopausal status (adjusted by age, age at first birth/nulliparity, age at menarche, height and weight)

Also in 2010, a group of researchers in Austria evaluated the relationship of intraepithelial neoplasia III (CIN-III) and invasive cervical cancer (ICC) with GGT. This relationship was studied, "in a prospective population-based cohort of 92,843 women ages 18 to 95, of whom 79% had at least one gynecologic examination including Pap smear testing during follow-up. This investigation found that, "during median follow-up of 13.8 years, 702 CIN-III and 117 ICC diagnoses were observed. Compared with normal low GGT (<17.99 units/L),risk of ICC was significantly elevated for all other baseline GGT categories, with adjusted HRs of 2.31(1.49-3.59) for normal high GGT (18.00-35.99 units/L),2.76(1.52-5.02)for elevated GGT(36.00-71.99 units/L), and 3.38 (1.63-7.00) for highly elevated GGT [>72.00 units/L;P trend < 0.0001, HR log unit increase 3.45 (1.92-6.19)]. In other words, above low normal GGT of ~ 18/U/L, the risk of Invasive Cervical Cancer increased in direct proportion to other higher GGT levels, including normal high and highly elevated. The researchers concluded, "Our findings implicate GGT in the progression of premalignant cervical lesions to invasive cancer." [Healthy-e-Iron note: Figure 1 and Table 5 from this study are below]

Figure 1. Kaplan-Meier estimates of cumulative incidence of CIN-III (A) and ICC (B) according to categories of serum GGT, measured at baseline. For the analysis of CIN-III, women with one or more gynecologic examinations during follow-up were included (n = 73,354); for the ICC analyses, all women were included (n = 92,843).

In 2008, this team of Austrian investigators noted, "Although several epidemiologic studies have shown that gamma-glutamyltransferase (GGT) is associated with cardiovascular disease and all-cause mortality, its relationship with cancer incidence remains widely unexplored." "...We investigated the association of GGT with overall and site-specific cancer incidence in a population-based cohort of 92,843 Austrian women with 349,674 serial GGT measurements, prospectively followed-up for a median of 13.5 years." "During follow-up, 4,884 incidence cancers were observed. Compared to normal low GGT (<17.99 U/L), cancer risk was elevated for all other GGT categories (p for trend < 0.0001), with adjusted hazard ratios(95% confidence intervals) of 1.06 (0.99-1.13) for GGT levels between 18.00 and 35.99 U/L (normal high), 1.12 (1.02-1.22) for GGT levels between 36.00 and 71.99 U/L (elevated) and 1.43 (1.28-1.61) for highly elevated GGT (>72.00 U/L). In other words, overall cancer risks increased 6-43% in proportion to increasing GGT measures in women when GGT was above ~ 18/U/L. The researchers concluded, "Our study is the first to demonstrate in a large population-based cohort that high GGT levels significantly increased cancer risk in women." [Healthy-e-Iron note: Figure 1 from this study is below]

FIGURE 1 – Adjusted cumulative overall cancer incidence according to baseline GGT levels among 92,843 female Austrian adults (mean age 41.7 years) in the VHM&PP. Curves were estimated at the average values of covariates using Cox proportional hazards models adjusted for body-mass index, smoking status, occupational status and year at entry into the cohort.

[Health-e-Iron note: a slide presentation from the authors of the above research can be viewed by clicking on thisLINK]

In the same study described directly above, the investigators "... prospectively investigated the association between GGT and risk of overall and site-specific cancer incidence in a large population-based cohort of 79,279 healthy Austrian men with serial GGT measurements. Median follow-up was 12.5 years." "In comparison with the reference GGT concentration (25 units/L), we found adjusted relative risks (95% confidence intervals) equalling 1.19(1.15-1.22) for GGT concentrations of 60 units/L, 1.32(1.28-1.36) for 100 units/L, 1.67 (1.60-1.75) for 200 units/L, and 2.30(2.14-2.47) for 400 units/L." GGT lab references are higher for men than for women. However here, the investigators found overall cancer risks increased 32-130% in proportion to increasing GGT measures in men when GGT was above ~ 18/U/L. The investigators noted,"Age of participants significantly modified the association of GGT and cancer risk(P < 0.001),revealing markedly stronger associations in participants less than 65 years of age." [Healthy-e-Iron note: Figures 1 and 3 from this study are below]

Figure 1. Adjusted cumulative cancer incidence according to quintiles of log GGT at first examination among 79,279 male Austrian adults (mean age, 41.6 y) in the VHM&PP estimated at the average values of covariates. Survival curves were calculated from Cox proportional hazards models adjusted for age, BMI, smoking status, occupational status, and year of examination.

This abstract describes a U.S. laboratory investigation of GGT expression in 451 human malignancy sites. "There was no GGT expression in mesotheliomas, Hodgkin's disease, non-Hodgkin's lymphomas, melanomas, basal cell carcinomas, and most soft tissue sarcomas..."...GGT was expressed in 22 of 44 lung carcinomas and 16 of 22 ovarian surface epithelial carcinomas,...""Carcinomas arising from some GGT-positive epithelium retained their GGT-positive phenotype. These included renal cell carcinomas, hepatocellular and cholangiocarcinomas, and carcinomas of the prostate and thyroid whereas both pancreatic adenocarcinomas and infiltrating carcinomas of the breast showed a wide range of GGT expression."

In this 1999 laboratory study, the investigator describes observations of the inverse relationship between GGT and glutathione in cultured mouse liver cells. In what is described asthe medium of GGT-positive cells, no glutathione was found. The converse finding was attributed to "GGT-negative" cells. Glutathione is an important antioxidant. This research noted from previous findings that, "GGT-positive cells grow more rapidly than the GGT-negative cells when transplanted into animals."

A second 1999 study on the relationship of accelerated tumor growth and GGT by the lead investigator of the directly-above study reported that "...when the (tumor) cells were injected into nude micethe GGT-positive tumors grew at more than twice the rate of the GGT-negative tumors." "The GGT-positive tumors were significantly more resistant to the toxicity of cisplatin(a chemotherapy drug) than the GGT-negative tumors. Therefore, expression of GGT is required for the nephrotoxicity of cisplatin, but diminishes the tumor toxicity of the drug." [Healthy-e-Iron note: Figure 1 from this study is below]

The following background was provided in this 2012 study, "GGT, a known marker for apoptotic balance, seems to promote tumour progression, invasion and drug resistance. Recently, high GGT serum levels were shown to be associated with impaired prognosis in patients with cervical cancer." In a muli-center trial in Austria, "Patients were stratified in GGT risk groups, and univariate and multivariable survival analyses were performed.Results: Mean pre-therapeutic serum GGT level was 30.8 (41.5) U l(-1).Elevated and highly elevated serum GGT levels(P=0.03 and P=0.005), tumour stage (P<0.001 and P<0.001), grade (P<0.001 and P=0.02) and age (P<0.001 and P<0.001) were independently associated with progression-free survival in univariate and multivariable survival analyses. The researchers concluded, "Pre-therapeutic serum GGT is a novel and independent prognostic parameter forprogression-free survivalof patients with endometrial cancer. Stratifying patients into prognostic subgroups could be used for patient counselling and individualised treatment planning."

This was a 2013-reported study from Austria. "The aim of this study was to assess the extent of the association between lifestyle-related biomarkers and the survival of endometrial cancer patients. Methods: A sub-cohort of 242 endometrial cancer patients, from a population-based study of the more than 90,000 female participants of the Vorarlberg Health Monitoring and Promotion Programme, was followed for a median duration of twelve years. Besides age, tumour staging, and histology, also pre-diagnostic levels of bodymass index, blood pressure, triglycerides, total cholesterol, glucose, gamma-glutamyltransferase (GGT), and serum uric acid were analysed in Cox proportional hazards regression models to estimate multivariate mortality risks. Results: During follow-up 89 deaths occurred of which 49 were cancer-related. Survival was associated with age, tumour stage, and histology. Of the biomarkers, log(10)-transformed GGT showed a large effect on cancer-related mortality (HR=3.35, 95% CI 1.12-10.03), whereas the other parameters did not appear with significant effects after adjustment for the other factors. Conclusion: Elevated level of GGT, a lifestyle-related marker, was associated with poor survival among endometrial cancer patients."

In this 2011 study reported by investigators from Memorial Sloan-Kettering Cancer Center, New York, in a multi-center trial, "pre-therapeutic GGT levels were examined in 692 patients with cervical cancer. GGT levels were correlated with clinico-pathological parameters." "We (further) investigated the association between prognosis and GGT and observed a linear correlation between GGT and prognosis.Therefore we were not able to identify a clear prognostic cut-off value for GGT in patients with cervical cancer." The investigators concluded, "High GGT--a marker for apoptosis and cervical cancer risk--is associated with advanced tumor stage in patients with cervical cancer."

This 2011 Brazilian study describes observations of oxidative stress and tissue damage in early and advanced stage breast cancers. "Analysis of the results verified different oxidative stress statuses occur at distinct cancer stages." Early disease was characterized by (among other things) reduced antioxidants (including glutathione) and lipid peroxidation. Advanced disease patients exhibited more pronounced levels of oxidative stress and intense lipid peroxidation."Plasma iron levels were significantly elevated in AD(advanced disease)." "The data obtained indicated that oxidative stress enhancement and immune response impairment may be necessary to ensure cancer progression to advanced stages and may result from both host and tumor inflammatory mediators."

This study was reported in 2009 by researchers at Vanderbilt Epidemiology Center. The study noted that "Increased reactive oxygen species may exhaust the antioxidant capability of human defense systems, leading to oxidative stress and cancer development." "We conducted a nested case-control study within the Shanghai Women's Health Study, a population-based cohort study of 74,942 Chinese women between 40 and 70 years of age. Prediagnostic urinary 15-F(2t)-IsoP and 15-F(2t)-IsoPM were measured by gas chromatography mass spectrometry for 436 breast cancer cases and 852 individually matched controls." "Urinary excretion of isoprostanes was not significantly different between cases and controls. However, among overweight women, levels of isoprostanes were positively associated with breast cancer risk, which became stronger with increasing body mass index (BMI). Among women with a BMI > or = 29, the odds ratio (OR) increased to 10.27 (95% CI, 2.41 to 43.80) for the highest compared with the lowest tertile of 15-F(2t)-IsoPM (P for trend = .003; P for interaction = .0004)." The researchers concluded, "Our results suggest that the role of oxidative stress in breast cancer development may depend on adiposity." [Health-e-Iron note:Figure 2 from this study is below. Also, elevated iron and elevated GGT both correlate with obesity]

In this 2011 study, the researchers described the background for their work as follows: "Apart from using gamma-glutamyltransferase (GGT) as a predictor of diabetes, cardiovascular and chronic kidney disease, some evidence suggests GGT as an indicator of cancer risk. We aimed to study the association between GGT and cancer in a large Swedish cohort with 37,809 primary cancers." "In a cohort of 545,460 persons (aged >20 years) ... (we) investigate(d) categories of GGT (<18, 18-36,36-72, ≥72 U/L) in relation to cancer risk." "A positive association was found between categories of GGT and overall cancer risk (HR: 1.07(95%CI: 1.04-1.09,), 1.18 (1.14-1.22), 1.32(1.26-1.38) for the2nd, 3rd and 4th categories compared to the 1st). Stratified analyses showed that for those with glucose ≥6.11 mmol/L, the association between GGT and risk of prostate, breast and liver cancer became stronger (e.g. HR forGGT ≥72 U/L and prostate cancer: 1.11 (0.98-1.26) and 1.35(1.00-1.81) forglucose <6.11 and≥6.11 mmol/L, respectively). The researchers concluded, "We found evidence of associations between elevated GGT and risk of developing different cancers. The strength of this association may vary by glucose levels becausehyperglycaemiacan result in oxidative stress initiating damaging pathways of carcinogenesis." [Healthy-e-Iron note: a graphic derived from these findings is below]

In this study of serum blood factors indicated that cancer patients with elevated GGT and several other serological factors "were significantly higher in patients with liver metastasis than in those without liver metastasis." The "cut point" for GGT was 30 U/L, a measure well-within normal laboratory ranges. The researchers concluded, "Early diagnosis of liver metastasis is of great significance...." [Healthy-e-Iron note: Figure 1 and Table 4 from this study are below]

The complete abstract of this 2010 review follows: "Gamma-glutamyltransferase (GGT) is a key enzyme involved in glutathione metabolism and whose expression is often significantly increased in human malignancies. In the past years, several studies focused on the possible role ofGGT in tumor progression, invasion and drug resistance. The involvement of a pro-oxidant activity of GGT, besides its early recognized contributions to cellular antioxidant defenses, has been repeatedly documented. GGT-derived pro-oxidants can modulate important redox-sensitive processes and functions of the cell, with particular reference to its proliferative/apoptotic balance, which has obvious and important implications in tumor progression and drug resistance. In addition, the specificity of the enzymatic reaction carried out by GGT suggests that suitable pro-drugs could be selectively metabolized (activated) by GGT expressed in tumor tissue. This paper is a review of the recent investigation in the field, focusing on the potential role of GGT as a diagnostic/prognostic marker, as well as a target for anticancer treatments."

The complete abstract of this 2010 review follows: "Abstract In clinical practice, increased serum gamma-glutamyltransferase (GGT) activity is usually interpreted as a marker of alcohol abuse and liver dysfunction. The knowledge of the GGT's physiological functions has expanded and several important epidemiological associations have been reported. This review examines evidence for an association of high normal serum GGT enzyme activity, mostly within the reference range, with the risk of mortality and major vascular (i.e., cardiovascular morbidity and mortality) and non-vascular outcomes (i.e., incident type 2 diabetes, chronic kidney disease and cancer), independent of alcohol consumption and other prognostic factors."

These researchers investigators studied serum markers of liver injury and "12-year mortality among 14,950 adult participants in the third US National Health and Nutrition Examination Survey, 1988-1994, who were negative for markers of viral hepatitis B and C. Abnormal ALT was defined as >30 U/L in men or >19 U/L in women, and abnormal GGT as >51 U/L in men or >33 U/L in women." Only GGT was associated with all-cause mortality, including from liver disease, cancer and diabetes. "The risk of all-cause mortality was 60% higher among persons with elevated GGT in age-adjusted analysis,and adjusting for multiple factors had little effect on this relationship. For CVD mortality, the HR for persons with elevated GGT was increased in age-adjusted analysis (HR, 1.5; 95% CI, 1.05–2.0): however, the risk was diminished in multivariate-adjusted analysis and no longer reached statistical significance (HR, 1.3; 95% CI, 0.80 –2.0)." "Elevated GGT was associated with a 50% higher risk of cancer mortality in both age-adjusted and multivariate-adjusted analyses. For diabetes mortality, GGT elevation was associated with almost 5 times the risk in age-adjusted analysis and more than 3 times the risk after adjusting for multiple factors, but not baseline glucose status. Similarly to ALT, GGT activity was strongly associated with diabetes at baseline,..." "For liver disease mortality, GGT elevation was associated with 19 times the risk ... in age-adjusted analysis ... The risk remained increased 13-fold with adjustment for additional factors (P = .004)." "The researchers concluded, "In the US population, elevated GGT was associated with mortality from all causes, liver disease, cancer, and diabetes, while ALT was associated only with liver disease mortality."

This 2009 study provides a good description of the interaction of GGT with catalytic iron. The complete abstract follows: " A number of recent observations have suggested a potential role for membrane-bound gamma-glutamyltransferase (GGT) in tumor progression and appearance of more aggressive and resistant phenotypes, through redox interactions leading to production of reactive oxygen species. The present study was aimed to evaluate whether such pro-oxidant activity of GGT can promote oxidative DNA damage, thus contributing to cancer genomic instability. Human GGT-transfected melanoma cells were studied, and DNA damage was measured by using the alkaline comet assay.Our results indicate that higher levels of GGT activity are associated with higher levels of background DNA damage and oxidized bases. This association cannot be explained by differences in cell cycle distribution or apoptotic rates.GGT-over-expressing cells also presented with a markedly higher glucose uptake, a phenomenon potentially leading to higher metabolic rate and oxidative DNA damage. Anyway, when GGT-over-expressing cells were incubated in the presence of GGT substrates and a source of catalytic iron, increased levels of DNA damage and oxidized bases were observed, an effect completely prevented in the presence of GGT inhibitors or various antioxidants.The findings reported indicate that GGT activity is able to promote iron-dependent DNA oxidative damage, thus potentially representing an important mechanism in initiation/progression of neoplastic transformation."

In this Serbian study, GGT levels of 216 cancer patients (156 patients with localized renal cell carcinoma and 60 patients with metastases as proven by echosonography) were compared to those of 50 healthy controls. "GGTactivities were normal in majority of patients with localized renal cell carcinoma and increased in most of the patients with metastatic disease..." The researchers concluded, "Our data provided evidence that GGT is a sensitive marker of metastatic renal cell carcinoma. However, findings of abnormal GGT activity cannot specify the site of involvement." [Healthy-e-Iron note: Figure 1 from this study is below]

This is an animal study completed in China. The researchers "found that liver GGT was over-expressed and secreted into blood during canceration. Serum total GGT and liver GGT specific activities (IU/g) including soluble and membrane-combined GGT were significantly higher (P<0.05) in experimental groups than those in control group, respectively." The researchers concluded, "Fetal liver-type GGT in sera and the liver of rats is closely related to hepatotumorigenesis. It can be used as a sensitive enzymatic marker for the early diagnosis of liver cancer."

This 2003 reported study in Italy "... aimed at verifying the possibility that GGT-mediated iron reduction may participate in the process of cellular iron uptake." In this laboratory study of four distinct human tumor cell lines, exhibiting different levels of GGT activity, were studied. The uptake of transferrin-bound iron was investigated..." The researchers concluded, "...that membrane GGT can represent a facilitating factor in iron uptake by GGT-expressing cancer cells, thus providing them with a selective growth advantage over clones that do not possess the enzyme." [Healthy-e-Iron note: Figure 1 from this study is below]

This research group from China identified three types of GGT messenger RNAs in liver tissue and peripheral blood. Bases on laboratory findings, the investigators concluded, "the analysis of GGT gene may provide a useful tool for early diagnosis of HCC(liver cancer)."

This research team in France reviewed stated, "...in recent years, findings from our group and from others showed that GGT-catalysed extracellular metabolism of GSH leads, in the presence of iron, to the generation of reactive oxygen species (ROS). "The objective of the present work is to determine whether the red blood cells are targets for plasma GGT-initiated pro-oxidant reaction" And, "The results obtained demonstrate that the GGT/GSH/iron system oxidises isolated erythrocyte membranes. A significant release of haemoglobin and a decrease of erythrocyte deformability are also observed." The researchers concluded, "GGT-mediated ROS production is able to oxidise erythrocytes and thus disturbs their functions."

This 1998 laboratory study identified and further confirmed that GGT,through a product formed in GGT/glutathione reaction, "was responsible for ROS formation initiated by the reductive release of iron from transferrin." The researchers concluded,"These data clearly indicate that under physiological conditions, GGT is directly involved in ROS generation."

In this 2002 study of the biochemistry of the interaction of GGT with glutathione, these Norwegian scientists discerned that "depletion of glutathione alone did not alter GGT activity."They concluded, "Apparently, the regulation of the enzyme is not directly linked to the intracellular level of glutathione."

This 2012-reported laboratory study was preformed in Turkey. "Several studies have documented that formation of oxidant mediators may induce apoptosis in nucleated and anucleated cells by modulating intracellular signalling pathways. Reactive oxygen species (ROS) play a very important role in the platelet function. γ-Glutamyltransferase (GGT), a novel source of cellular production of oxidants in the presence of iron and reduced glutathione (GSH), is also found on platelets. The role of platelet-bound GGT in platelet apoptosis and oxidative stress is unknown. The aim of our study was to determine the effects of platelet GGT activity on oxidative stress and apoptotic events in vitro via determination of lipid peroxidation (LPO), protein oxidation, GSH, catalase, caspase-3 activation and phosphatidylserine (PS) exposure in the presence of holo-transferrin (Tf). Stimulation of platelet GGT activity with GSH and glycylglycine (GlyGly) increased caspase-3 activation and PS exposure.A significant increase in lipid and protein oxidation and decrease in GSH and catalase levels was also observed in platelets with stimulation of GGT activity in the presence of Tf. Inhibition of GGT activity effectively reduced all the markers." The researchers concluded, "These results suggest that generation of ROS by the GGT/GSH/Tf system can modify the platelets' redox environment and induce apoptosis in in vitro conditions."

This 2000 laboratory study was reported from France. "It has been previously reported that the metabolism of reduced glutathione (GSH) by gamma-glutamyltranspeptidase (GGT) in the presence of chelated metals leads to free radical generation and lipid peroxidation (LPO). The present study demonstrates for the first time that an established cell line expressing GGT-rel, a human GGT-related enzyme, metabolizes extracellular GSH to cysteinylglycine (CysGly) in a time-dependent manner when cells were incubated in a medium containing 2.5 mM GSH and 25 mM glycylglycine. Supplementation with 150-165 microM Fe(3+)-EDTA resulted in a reactive oxygen species (ROS) generation process. The resulting data showed a significantly higher level (7.6-fold) of ROS production in the GGT-rel positive cells in comparison with the GGT-rel negative control cells. CysGly and Cys, but not GSH, were responsible for the observed ROS production, as we confirmed by measuring the same process in the presence of Fe(3+)-EDTA and different thiols. A higher iron reduction and an increased LPO level determined by malondialdehyde HPLC measurement were also found in GGT-rel-overexpressing cells compared to GGT-rel negative cells. The researchers concluded, "Our data clearly indicate that in the presence of iron, not only GGT, but also GGT-rel has a pro-oxidant function by generation of a reactive metabolite (CysGly) and must be taken into account as a potential physiopathological oxidation system."

Following this 2002 study of the molecular and cellular GGT/glutathione interaction in mice, the researchers concluded, "Our results indicate that tumor GGT activity and an inter tissue flow of GSH can regulate GSH content of melanoma cells and their metastatic growth in the liver."

The complete abstract of this 2001 review follows: "Serum gamma-glutamyl transferase (GGT) has been widely used as an index of liver dysfunction and marker of alcohol intake. The last few years have seen improvements in these areas and advances in understanding of its physiological role in counteracting oxidative stress by breaking down extracellular glutathione and making its component amino acids available to the cells.Conditions that increase serum GGT, such as obstructive liver disease, high alcohol consumption, and use of enzyme-inducing drugs, lead to increased free radical production and the threat of glutathione depletion. However, theproducts of the GGT reaction may themselves lead to increased free radical production, particularly in the presence of iron. There have also been important advances in the definition of the associations between serum GGT and risk of coronary heart disease, Type 2 diabetes, and stroke. People with high serum GGT have higher mortality, partly because of the association between GGT and other risk factors and partly because GGT is an independent predictor of risk." "This review aims to summarize the knowledge about GGT's clinical applications, to present information on its physiological roles, consider the results of epidemiological studies, and assess how far these separate areas can be combined into an integrated view."

This study suggests an explanation of how "expression of GGT activity can provide melanoma cells with an additional source of hydrogen peroxide, and that such prooxidant reactions are capable to modify protein thiols at the cell surface level. In addition, GGT expression results in an up-regulation of the transcription factor NF-kappa B, which could explain the higher metastatic behaviour reported for GGT-rich melanoma cells as compared to their GGT-poor counterparts."

This paper describes a "third functional aspect of GSH (glutathione), i.e. the prooxidant roles played by molecular species originating during its catabolism by the membrane ectoenzyme gamma-glutamyl transpeptidase (GGT). "The reduction of metal ions effected by GSH catabolites is capable to induce redox cycling processes leading to the production of reactive oxygen species (superoxide, hydrogen peroxide), as well as of other free radicals."

This 1994 study examined GGT expression in primary human ovarian tumors. "GGT was expressed in some epithelial inclusion glands and occasionally in a small subset of stromal cells. Granulosa-stromal cell tumors were largely GGT-negative. In contrast, GGT-positive neoplastic cells were observed in 33 of 45 common epithelial ovarian tumors. None of the patients had been treated with chemotherapy. Some of the tumors had only rare GGT-positive cells, while others consisted almost entirely of GGT-positive cells."At the time of this "early" study, researchers had not yet determined if "expression of GGT serves as a marker for identifying neoplasms with enhanced resistance to platinum-based therapy." [Health-e-iron note: more current studies support the opinion that it does]

The results of this 2010 genome-wide association study indicated that a variation of the GGT 1 gene "has been reported to be associated with increased GGT1 serum levels." And, "GGT is expressed in the pancreas and plays a key role in glutathione metabolism."The researchers concluded, "Our results suggest that common variation in the GGT1 gene may affect the risk of pancreatic cancer."[Health-e-Iron note: we suggest reading the highlighted text on journal page 199 of the "Free full text" for a good summary discussion. We have also copied and pasted this section below (without citation reference numbers).]

"GGT is also present in bodily fluids, and serum GGT levels are clinically commonly used as an indicator of liver disease or marker of excessive alcohol intake. However, elevated GGT levels have also been found associated with various other diseases, including cardiovascular disease, and serum GGT has been proposed as a marker of oxidative stress. Importantly, Strasak et al. recently reported that elevated GGT serum levels were significantly associated with increased cancer risk in men and women in a large population-based cohort. Associations between serum GGT levels and risk of pancreatic cancer specifically have, to our knowledge, not yet been investigated."

"The relationship between serum GGT and membranebound GGT is unknown, but increased serum levels plausibly reflect increased expression. Membrane-bound GGT catalyzes the transfer of the -glutamyl moiety from glutathione and other -glutamyl compounds to acceptors. As such, it plays a key role in maintaining intracellular glutathionelevels which is critical for phase II reactions and the detoxification of reactive metabolites and xenobiotics. Paradoxically, in the presence of iron or other transition metals, the extracellular cleavage of glutathione by GGT can also result in the generation of reactive oxygen species, free radicals, and oxidative damage. Moreover, (over)expression of GGT may promote tumor progression and drug resistance by protecting cells from oxidative stress-associated apoptosis. Thus, functionally relevant polymorphisms in GGT1 may well affect the risk of developing cancer in tissues that express GGT."

In this 2009 review the authors stated, "It was previously hypothesized that serum gamma-glutamyltransferase (GGT) within its reference range predicts various clinical outcomes as a sensitive marker of oxidative stress in humans. This study further hypothesizes that serum GGT can mark exposure to various environmental pollutants, based both on recent epidemiological findings and on well-established biochemical features of cellular GGT. Cellular GGT is a prerequisite for metabolism of GSH conjugates that detoxify xenobiotics to mercapturic acid. Under this concept, serum GGT may increase with increasing exposure to environmental pollutants which need to be conjugated to GSH. Supporting this concept, it was recently reported that serum GGT within its reference range was linearly associated with important environmental pollutants, including lead, cadmium, dioxin and organochlorine pesticides. As a marker of the amount of conjugated xenobiotics, recent epidemiological findings about serum GGT imply the possibility of harmful effects of various environmental pollutants at background levels currently regarded as safe."

The authors of the above paper also published the results of this study in 2009. "We recently hypothesized that serum gamma-glutamyltransferase (GGT), within its reference range, predicts many diseases as a biomarker for background exposure to various xenobiotics. Even though normal serum GGT was associated with xenobiotics having very long half-lives (heavy metals, dioxin, or organochlorine pesticides), it was unknown whether GGT was associated with xenobiotics with short half-lives, including polycyclic aromatic hydrocarbons (PAHs), well known carcinogens" "Among 1,256 adult participants in the National Health and Nutrition Examination Survey (NHANES) 2003-2004, urinary metabolites of PAH (monohydroxy-PAH), and serum GGT were measured. We selected the 10 monohydroxy-PAHs (OH-PAHs) for which at least 90% of participants had concentrations greater than the limit of detection." "Among the 10 OH-PAHs,eight had significant positive correlations with serum GGT. These correlations were similarly observed in men and women, and in individuals under 60 years of age. Unlike serum GGT, alanine aminotransferase, another liver enzyme, was not associated with OH-PAHs." The researchers concluded, "Taken together with the previous epidemiological evidence, the associations of serum GGT with OH-PAHs reinforce the concept that serum GGT is a marker for various environmental pollutants encountered at background levels in the general population."

This a 2012 comprehensive review and discussion of the autophagic process, and its relation to human disease. "The present review highlights recent studies on redox signalling in the regulation of autophagy, in the context of the basic mechanisms of mitophagy. Furthermore, we discuss the impact of autophagy on mitochondrial function and accumulation of reactive species.This is particularly relevant to degenerative diseases in which oxidative stress occurs over time, and dysfunction in both the mitochondrial and autophagic pathways play a role."

This 2012 published study was reported by researchers at Thomas Jefferson University, Philadelphia.The researchers noted, "Large observational studies indicated that these enzymes might predict cancer risk and mortality. However, no prospective study has reported on their relationships with the risk of HBV-related hepatocellular carcinoma (HCC).""We evaluated the predictive values of four routinely tested liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and gamma-glutamyltransferase [GGT]) in HCC risk in a prospectively enrolled clinical cohort of 588 Korean American HBV patients. For all four enzymes, the baseline level as well as the average and maximum levels during the first 1 or 2 years of follow-up were analyzed using multivariate Cox proportional hazards model. Patients were categorized into a normal or an elevated group based on the clinical cut-off of each enzyme. During a median follow-up of 7.5 years, 52 patients (incidence rate, 8.8%) developed HCC. The incidence rates were higher in the elevated groups for all four enzymes. The most significant finding was for GGT, with the highest incidence rate of 16.4% in the elevated group compared to 4.6% in the normal group (P<0.001). Compared to patients with normal baseline GGT, those with elevated GGT exhibited a significantly increased HCC risk with a hazards ratio (HR) of 2.60 (95% confidence interval [CI], 1.41-4.77, P = 0.002). Further analyses revealed a cumulative effect between baseline GGT and ALP (HR = 3.41, 95% CI 1.54-7.56, P = 0.003)."The researchers concluded, "Serum GGT might predict HCC risk in HBV patients individually or jointly with other enzymes." [Health-e-iron note: Figure #1 from this study is below]

In this 2011 study of the relevance of GGT levels to various factors affecting survival in hepatocellular cancer (HCC) patients, the effectiveness of transcatheter arterial chemoembolization (TACE), and the prognostic significance of GGT. "High GGT, correlating with higher tumor size, α-fetoprotein (AFP), and alanine aminotrasferase, was an independent prognostic factor for Overall Survival (P=0.009)."The researchers concluded, "GGT level was an important prognostic factor to predict prognosis of patients with intermediate HCC treated with TACE."

Researcherswho earlier in 2012 published their findings relative to a biomarker-based scoring system they applied for participants in the Swedish AMORIS study published this paper based on the application of the same biomarker scoring system to this large U.S. cohort. "Baseline measurements of CRP, albumin, GGT, and HDL were available for participants with mortality follow-up (n=13,056). A biomarker score, ranging 0--4, was created by adding number of markers with abnormal values (cut-off: CRP>10mg/L, albumin<35mg/L, GGT>36U/L, HDL<1.04mmol/L). Its association with mortality was analyzed with multivariate Cox proportional hazards models." "The score was positively associated with death from all causes, cancer and circulatory disease [e.g. HR all-cause mortality: 1.21 (95% CI: 1.09, 1.35), 1.92 (1.67, 2.20), 3.38 (2.62, 4.36), and 7.93 (5.77, 10.89), for score 1, 2, 3,4 vs.0]. These patterns were found across the Charlson Comorbidity Index (CCI). Where CCI =3, risk of cancer death was 1.09 (0.93, 1.28), 1.81 (1.43, 2.29), 4.67 (3.05, 7.14), and 6.97 (5.32, 9.14) for score 1, 2, 3, 4vs. 0. No effect-modification by sex or race/ethnicity was observed. The researchers concluded, "These findings correlate with results from a Swedish study. This biomarker-based score could help clinicians make decisions in prevention and disease management."

This 2012-reported study was undertaken as part of the large prospective study in Sweden referenced in the above U.S. study. The researchers noted, "Recent studies suggested that gamma-glutamyl transferase (GGT) and C-reactive protein (CRP) are good markers of metabolic abnormalities. We assessed the link between GGT, CRP and common metabolic abnormalities, as well their link to related diseases, such as cancer and cardiovascular disease (CVD)." "We selected 333,313 subjects with baseline measurements of triglycerides (TG), total cholesterol (TC), glucose, GGT and CRP in the Swedish AMORIS study. Baseline measurement of BMI was available for 63,900 persons and 77,944 had baseline measurements of HDL. Pearson correlation coefficients between CRP, GGT, and metabolic components (TG, HDL, BMI and TC) were calculated. To investigate the combined effect of GGT and CRP we created a score ranging from 0 to 6 and used Cox proportional hazard models to evaluate its association with CVD and cancer." "21,216 individuals developed cancer and 47,939 CVD. GGT and TG had the strongest correlation (r=0.22). An increased risk of cancer was identified with elevated levels of GGT or CRP or both markers (GGT-CRPscore ≥3); the greatest risk of cancer was found when GGT-CRP score = 6 (HR: 1.40 (95%CI: 1.31-1.48) and 1.60 (1.47-1.76) compared to GGT-CRP score = 0, respectively)." The researchers concluded, "While GGT and CRP have been shown to be associated with metabolic abnormalities previously, their association to the components investigated in this study was limited. Results did demonstrate that these markers were predictive of associated diseases, such as cancer." "This area would benefit from intervention studies aimed to determine whether lifestyle changes could reduce GGT and CRP levels and subsequently the risk of abnormal metabolic profiles and associated diseases."

The researchers of this 2013-reported study noted, "Biomarkers have been utilized for prognosis in colorectal cancer, relatively few have been identified. We compared the prognostic value of serum alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and γ-glutamyl transpeptidase (GGT) with carcinoembryonic antigen (CEA) and carbohydrate entigen 19-9 (CA 19-9) in patients with metastatic colorectal cancer (mCRC)." "CEA (p<0.001), CA19-9 (p<0.001), GGT (p<0.001), ALP (p<0.001) and LDH (p=0.001) were statistically significant prognostic factors of overall survival(OS). CEA (p=0.002) and GGT (p=0.021) were validated as independent predictors." "On univariate analysis CEA (p=0.003), CA19-9 (p=0.006), GGT (p<0.001) and ALP (p=0.001) were statistically significant predictive factors of progression free survival(PFS) in patients having first-line chemotherapy. CEA (p=0.011) and GGT (p=0.027) were independent. GGT(p=0.001), ALP (p=0.016) and LDH (p=0.039) levels were correlated with the tumour response rate assessed by computerized tomography (CT), while CEA (p=0.724) and CA19-9 (p=0.822) were not. There was a statistically significant difference in OS (p<0.001) and PFS (p<0.001) among patients who had elevations of both CEA and GGT compared with those having only one or neither elevated." The researchers concluded, "Among GGT, LDH, and ALP, only GGT plays an independent role with CEA in predicting OS and PFS in mCRC. When coupled with CEA, GGT may lead to improved prognostic predictors."

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